Reagents have been designed and developed which can interact with nucleophilic residues on a protein chain by consecutive Micheal reactions to afford cross-linked structures. The reagents allow the formation of the most thermodynamically stable cross-link rather than the kinetic cross-link. Thus multiple cross-link can be introduced. The consecutive Michael reactions allow the reagent to "walk" along the protein chain. The chemistry of this process has been and continues to be explored in ribonuclease as well as insulin. Applications to lysozyme and papain are being initiated.